(a) Field of the Invention
The present invention provides novel compounds. In particular, this invention relates to novel octahydronaphthalenes of Formula XXVI.
The compounds of the present invention are useful as hypobetalipoproteinemic agents which are used to treat a mammal suffering from or susceptible to the development of an atherosclerotic disease.
Atherosclerosis in mammals is a disease characterized by the deposition of atherosclerotic plaque on arterial walls. Atherosclerosis exhibits many various forms and consequences. Typical consequences of atherosclerotic diseases include angina pectoris, mycardial infarction, stroke and transient cerebral ischemic attacks. Other forms of atherosclerotic diseases include certain peripheral vascular diseases and other ischemias (e.g., bowel and renal).
Medical science now recognizes that certain forms of atherosclerosis may be preventable or reversible. Agents capable of preventing or reversing atherosclerosis are characterized as exhibiting antiatherosclerotic activity. Since serum lipids have a recognized association with atherogenesis, an important class of antiatherosclerotic agents are those with serum lipid-modifying effects. Serum lipids implicated in atherogenesis include serum cholesterol, serum triglycerides, and serum lipoproteins.
With respect to serum lipoproteins, at least three different classes of these substances have been characterized; high-density lipoproteins (HDL's), low density lipoproteins (LDL's) and very low-density lipoproteins (VLDL's). HDL's are betalipoproteins. The control of LDL and VLDL levels (hypobetalipoproteinemic activity) is postulated to have a direct antiatherosclerotic effect. See Goodman and Gilman, The Pharmacological Basis of Therapeutics, fifth Ed. 744-752 (1975). The importance of lowering cholesterol levels may further be demonstrated by the availability of several commercial prescription products that are designed to lower cholesterol by several routes. See Physicians Desk Reference 1981, dextrothyroxine sodium pg. 898, clofibrate pg. 605, and cholestyramine pg. 1149. Several mechanisms of action have been described, for example, stimulation of the liver to increase catabolism and excresion of cholesterol, blocking the absorption of cholesterol in the intestine, and elimination by emulsification. The compounds of the present invention inhibit the production of cholesterol directly by interfering with HMG CoA reductase. This is beneficial in that serum liprotein levels of cholesterol are kept low without the need to eliminate excess cholesterol. The compounds of the invention are therefore also beneficial in cases of hypercholesterol production.
(b) Prior Art
The relationship between high blood cholesterol, atherosclerosis and medicament to control cholesterol are well known as described above. In addition it is known that 3-hydroxy-3-methylglutaryl-Coenzyme A reductase is the rate-limiting enzyme in the cholesterol synthetic pathway. Endo et al., described (U.S. Pat. Nos. 4,049,495 and 3,983,140) a fermentation product obtained by cultivation of a microorganism of the genus Penicillium, useful as an inhibitor in vivo of the biosythesis of cholesterol. Further, Monaghan, et. al. (U.S. Pat. No. 4,231,938), described certain lactones as well as their free hydroxy acids useful in the treatment of hypercholesteremia and hyperlipemia.